Adjuvant holmium-166 radioembolization after radiofrequency ablation in early-stage hepatocellular carcinoma patients: a dose-finding study (HORA EST HCC trial).

PURPOSE: The aim of this study was to investigate the biodistribution of (super-)selective trans-arterial radioembolization (TARE) with holmium-166 microspheres (166Ho-MS), when administered as adjuvant therapy after RFA of HCC 2-5 cm. The objective was to establish a treatment volume absorbed dose that results in an absorbed dose of ≥ 120 Gy on the hyperemic zone around the ablation necrosis (i.e., target volume). METHODS: In this multicenter, prospective dose-escalation study in BCLC early stage HCC patients with lesions 2-5 cm, RFA was followed by (super-)selective infusion of 166Ho-MS on day 5-10 after RFA. Dose distribution within the treatment volume was based on SPECT-CT. Cohorts of up to 10 patients were treated with an incremental dose (60 Gy, 90 Gy, 120 Gy) of 166Ho-MS to the treatment volume. The primary endpoint was to obtain a target volume dose of ≥ 120 Gy in 9/10 patients within a cohort. RESULTS: Twelve patients were treated (male 10; median age, 66.5 years (IQR, [64.3-71.7])) with a median tumor diameter of 2.7 cm (IQR, [2.1-4.0]). At a treatment volume absorbed dose of 90 Gy, the primary endpoint was met with a median absorbed target volume dose of 138 Gy (IQR, [127-145]). No local recurrences were found within 1-year follow-up. CONCLUSION: Adjuvant (super-)selective infusion of 166Ho-MS after RFA for the treatment of HCC can be administered safely at a dose of 90 Gy to the treatment volume while reaching a dose of ≥ 120 Gy to the target volume and may be a favorable adjuvant therapy for HCC lesions 2-5 cm. TRIAL REGISTRATION: Clinicaltrials.gov NCT03437382 . (registered: 19-02-2018).

Primary sclerosing cholangitis and other risk factors for post-transplant lymphoproliferative disease after liver transplantation in adults.

Post-transplant lymphoproliferative disease (PTLD) is a rare but serious complication of liver transplantation (LT) with morbidity and mortality. The risk factors for PTLD in adults are ill-defined. This study aimed to assess the risk factors for PTLD after LT in adults. All adult LT recipients between 1986 and 2016 from 2 centers in the Netherlands were included, with follow-up until 2020. PTLD was diagnosed according to the World Health Organization (WHO) classification. Potential risk factors for PTLD were assessed using multivariate Cox regression analysis. A total of 1281 patients were included, of whom 29 (2.3%) developed PTLD. Results show that independent risk factors for PTLD after LT in adults were no Epstein-Barr virus load monitoring strategy, primary sclerosing cholangitis as an indication for LT, era (historic era linked to more intense long-term immunosuppression), and Epstein-Barr virus-seronegative recipient. No other independent risk factors were identified in this study. Of the 207 patients with primary sclerosing cholangitis as an indication for LT, 13 (6.3%) developed PTLD versus 16 out of 1074 (1.5%) patients with other underlying liver diseases (log-rank p <0.001). The yearly PTLD incidence was higher in the first year than in the later years after LT (2.4%/y vs. 0.6%/y) for primary sclerosing cholangitis, but not for other indications (0.16%/y). In Epstein-Barr virus-seronegative recipients PTLD occurred earlier after LT, while in 97% of seropositive recipients it could occur very late after LT.

Randomized Trial of Ciclosporin with 2-h Monitoring vs. Tacrolimus with Trough Monitoring in Liver Transplantation: DELTA Study.

Background and Aims: Previous trials comparing cyclosporine and tacrolimus after liver transplantation (LT) showed conflicting results. Most used trough monitoring for cyclosporine (C0), leading to less accurate dosing than with 2-h monitoring (C2). Only one larger trial compared C2 with tacrolimus based on trough level (T0) after LT, with similar treated biopsy-proven acute rejection (tBPAR) and graft loss, while a smaller trial had less tBPAR with C2 compared to T0. Therefore, it is still unclear which calcineurin inhibitor is preferred after LT. We aimed to demonstrate superior efficacy (tBPAR), tolerability, and safety of C2 or T0 after first LT. Methods: Patients after first LT were randomized to C2 or T0. tBPAR, patient- and graft survival, safety and tolerability were the main endpoints, with analysis by Fisher test, Kaplan-Meier survival analysis and log-rank test. Results: In intention-to-treat analysis 84 patients on C2 and 85 on T0 were included. Cumulative incidence of tBPAR C2 vs. T0 was 17.7% vs. 8.4% at 3 months (p=0.104), and 21.9% vs. 9.7% at 6 and 12 months (p=0.049). One-year cumulative mortality C2 vs. T0 was 15.5% vs. 5.9% (p=0.049) and graft loss 23.8% vs. 9.4% (p=0.015). Serum triglyceride and LDL-cholesterol was lower with T0 than with C2. Incidence of diarrhea in T0 vs, C2 was 64% vs. 31% (p≤0.001), with no other differences in safety and tolerability. Conclusions: In the first year after LT immunosuppression with T0 leads to less tBPAR and better patient-/re-transplant-free survival as compared to C2.

Epstein-Barr Viral Load Monitoring Strategy and the Risk for Posttransplant Lymphoproliferative Disease in Adult Liver Transplantation : A Cohort Study.

BACKGROUND: Primary infection with or reactivation of Epstein-Barr virus (EBV) can occur after liver transplant (LT) and can lead to posttransplant lymphoproliferative disease (PTLD). In pediatric LT, an EBV-DNA viral load (EBV VL) monitoring strategy, including the reduction of immunosuppression, has led to a lower incidence of PTLD. For adult LT recipients with less primary infection and more EBV reactivation, it is unknown whether this strategy is effective. OBJECTIVE: To examine the effect of an EBV VL monitoring strategy on the incidence of PTLD after LT in adults. DESIGN: Cohort study. SETTING: Two university medical centers in the Netherlands. PATIENTS: Adult recipients of first LT in Leiden between September 2003 and January 2017 with an EBV VL monitoring strategy formed the monitoring group (M1), recipients of first LT in Rotterdam between January 2003 and January 2017 without such a strategy formed the contemporary control group (C1), and those who had transplants in Leiden between September 1992 and September 2003 or Rotterdam between 1986 and January 2003 formed the historical control groups (M0 and C0, respectively). MEASUREMENTS: Influence of EBV VL monitoring on incidence of PTLD. RESULTS: After inverse probability of treatment weighting of the 4 groups to achieve a balance among the groups for important patient characteristics, differences within hospitals between the historical and recent era in cumulative incidences-expressed as the number of events per 1000 patients measured at 5-, 10-, and 15-year follow-up-showed fewer events in the contemporary era in both centers. This difference was considerably larger in the monitoring center, whereas the 95% CI included the null value of 0 for point estimates. LIMITATION: Retrospective, low statistical power, and incompletely balanced groups, and non-EBV PTLD cannot be prevented. CONCLUSION: Monitoring EBV VL may reduce PTLD incidence after LT in adults; larger studies are warranted. PRIMARY FUNDING SOURCE: None.

Tacrolimus 4-hour monitoring in liver transplant patients is non-inferior to trough monitoring: The randomized controlled FK04 trial.

BACKGROUND: After liver transplantation (LT), tacrolimus and ciclosporin treatment can lead to, partially concentration-dependent, chronic kidney disease. Monitoring ciclosporin with two-hour levels reduced overexposure and led to better renal function than trough-monitoring (C0). For tacrolimus, a 4-hour level (C4) can give a reasonable approximation of total drug exposure. We evaluated whether monitoring tacrolimus in stable patients after LT by C4 was superior to C0 regarding renal function, rejection and metabolic parameters. METHODS: This open label randomized controlled trial compared C4 monitoring of tacrolimus BID (Prograft) to trough (C0) monitoring in stable LT recipients. The target range for C4 of 7.8-16 ng/ml was calculated to be comparable with target C0 of 4-8 ng/ml. Primary endpoint was the effect on renal function and secondary endpoints were the occurrence of treated biopsy-proven acute rejection, blood pressure and metabolic parameters, during 3 months of follow-up. RESULTS: Fifty patients were randomized to C0 (n = 25) or C4 (n = 25) monitoring. There was no difference in renal function between the C0 and the C4 group (p = .98 and p = .13 for CG and MDRD at 3 months). Also, the amount of proteinuria was similar (p = .59). None of the patients suffered from graft loss or was treated for rejection. Metabolic parameters did not differ between the two groups. CONCLUSION: Tacrolimus 4-hour monitoring in stable LT patients is not superior to trough monitoring, regarding the effect on renal function, but is safe for use to facilitate tacrolimus monitoring in an afternoon outpatient clinic.

Study Protocol: Adjuvant Holmium-166 Radioembolization After Radiofrequency Ablation in Early-Stage Hepatocellular Carcinoma Patients-A Dose-Finding Study (HORA EST HCC Trial).

PURPOSE: To investigate the biodistribution of holmium-166 microspheres (166Ho-MS) when administered after radiofrequency ablation (RFA) of early-stage hepatocellular carcinoma (HCC). The aim is to establish a perfused liver administration dose that results in a tumoricidal dose of holmium-166 on the hyperaemic zone around the ablation necrosis (i.e. target volume). MATERIALS AND METHODS: This is a multicentre, prospective, dose-escalation study in HCC patients with a solitary lesion 2-5 cm, or a maximum of 3 lesions of ≤ 3 cm each. The day after RFA patients undergo angiography and cone-beam CT (CBCT) with (super)selective infusion of technetium-99 m labelled microalbumin aggregates (99mTc-MAA). The perfused liver volume is segmented from the CBCT and 166Ho-MS is administered to this treatment volume 5-10 days later. The dose of holmium-166 is escalated in a maximum of 3 patient cohorts (60 Gy, 90 Gy and 120 Gy) until the endpoint is reached. SPECT/CT is used to determine the biodistribution of holmium-166. The endpoint is met when a dose of ≥ 120 Gy has been reached on the target volume in 9/10 patients of a cohort. Secondary endpoints include toxicity, local recurrence, disease-free and overall survival. DISCUSSION: This study aims to find the optimal administration dose of adjuvant radioembolization with 166Ho-MS after RFA. Ultimately, the goal is to bring the efficacy of thermal ablation up to par with surgical resection for early-stage HCC patients. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03437382.